Hydrogenated benz [cd] indoles



Patented Dec. 22, 1953 UNITED STATES ATENT OFFIfiZE HYDROGENATED BENZ [CD] INDOLES Edmund C. Kornfeld, Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis, Ind.,

a corporation of Indiana No llrawing. Applicationseptember 24, 1951, Serial No. 248,103\

7 Claims. (01. 26(I-3]i9) This invention relates to novel organic compounds and more particularly to hydrogenated benzEcdlindoles and their preparation.

The hydrogenated benZEcdIindoIes produced by means of the intermediate compounds and methods of this invention are represented by the following formula in which R represents H or a, carboxyacyl radical such as a radical of a lower aliphatic carboxylic acid or a monocyclic aromatic hydrocarbon car.- boXylie acid, and R1 represents hydrogen or as lower alkyl radical.

The above represented indole compounds'-are prepared by a series of reactions comprising the hydrogenation of indole-3-propionic acid and cyclization of an acid halide of the acylated hy,=-

drogenated compound with aluminum chloride drobenzfcdlindolez- Fromthe 'benzl-icdl indoie tiie ELiTormyIE com:--- pound,- which represented' by the foregoing foremula When-Rh is=hydrogengis obt'ainedz as; fol-:- lows:

COO

cinioon' The benz [ed]indole is reacted with 3; oil-10110;

acetic: acid ester in a, Darzens type reaction to;

produce aeglycidic compound which is hydrolysed to the sodium" salt of the glycidic acid. Reaction of the sodium salt with pyridine hydrobromide perbromi'de and treatment of the intermediate bromoaidehyde with semicarbazide yields i semicarbazone of an N-acyl-5-formyl-1,2,2a,3-tetra liydi obenzlcdlindole. Removal of the semicarbazide group yields an N-acyl-5-formyll,2,2a,3-

tetrahydroibenzlcdlindole, from whichzthe'N-acyl nitrile compound which upon reaction with hy- COOH cimo drogen chloride followed by treatment with collidine yields an N,5diacy1 compound from which the N-acyl group can be removed by hydrolysis.

The:v reactions; set; fOIYthw above; are: shown by meansv ofithe following-series; of; equations. which; for; thegsakewof-simplicity are limited to. the illuss tratiom of; the, reactions. leading; to; the; product-5- tionz. of: 5i-iormyle1 ,'2;2a;3-t etrahydrobenz[ed];

1116.016: and; 5 acetylel ,2;2a ;3;-: tetrahydrozenzlcd] indole.

GoHnC ON pg o 4 COON'a COOC'lHa CN -0 o OH NBOH CuHsC QN CoH.';DON- CGHsCON- v11 VI XIII Oollldine .HBLBN 0 CH3 v CHO CH=NNHCONH2 Br V H2NNHCONH:

CaHsCON- CdHgG C1 H5CON Vni IX XIV A020 NEOAC I CHaCOCOOH HOAC Ha CHO C O OH:

The above series of reactions is illustrative only, and obvious modifications will be apparent to those skilled in the art. Thus for example, although certain of the reactions as illustrated employ a particular aoyl halide or a particular carboxylic acid ester, other equivalent halides and esters can be employed.

The compounds of this invention are useful intermediates in the synthesis oi organic compoundshaving hydrogenated benzlcdlindole nuclei.- They are especially suitable for employment in syntheses of compounds having the ring systems of the ergot alkaloids, for example, lysergic acid. A few illustrative examples of the useful synthetic procedures in which the novel compounds of this invention can be employed are as follows:

N benzoyl 5 formyl l,2,2a,3 tetrahydrobenzicdlindole can be reacted with an mcyano or w-acetalyl-N-methyl-propyiarnine to yield, respectively, a nitrile or aldehyde containing the lysergic acid ring system. Hydrolysis and oxidation of the nitrile or aldehyde yield lysergic acid. Alternatively, the5 formyl compound. can be reacted with acetylene, the acetylenic oarbinol reacted with nickel carbonyl and the acrylv hydrobenz [cdlindole 0 C mLl CHO XVI

ic acid compound so produced reacted with methylamine and dehydrated to yield an N-benzoyiacid.

Reaction of N-benzoyl-5-acetyl-1,2,2a,3-tetrawith formaldehyde methylamine yields a cyclized product having a lysergic acid-like ring structure. Introduction of the oarboxyl group in a position corresponding to that in lysergic acid is accomplished by formylation followed by treatment with hydroxylarnine and base. Reduction and subsequent dehydration, hydrolysis and oxidation yields lysergic acid. Alternatively, the iormylation and treatment with hydroxylamine can precede the Mannich reaction, i. e. the reaction with formaldehyde and methylamine. A further synthesis of lysergic acid comprises reacting the E-acetyl compound with ethyloxalate and treating the oxalyl ketone with formaldehyde and methylamine by the procedure of the Mannich reaction.

anal-m The resulting, commoners redneethdehtdtetedi. deearhontlated. hydro ysed. and oxidized to; yield hrsergie aeid.

"the io low na examples. iurther i lustrate the methods; and: products: of ntent on...

EXAMPLE 1 N-benzoyl-5-keto-1,z,zla,3,4,5-hlexahydmbenzn edl ind ote A mixture of 118 g. (0.4 mol) of N-benzoylindoline-3-propionic ae-ijd, prepared according to the method of, Robinson J. Chem. Soc. l93l, 3158- and 20 Q* ml. Q1 thi'onyl chloride was allowed to stand at room temperature for V2 hour and was; warmed. on; a, steam. bath. forabout 20. minutea. exeess. thionyl. chloride was evapoe rated vaeua, and the residue N benaorlindoline-B p opionyl chloride, was dise solved in zoo m1.-. of. arbon. disulfidet The.

solution was added a thin stream to. a v gorously st r d suspension of 2.441 2,. Qt. a uminum ch or de n 1. .5.0. m1.- oi. oar on. disulfide. The. mixture wa refluxed and stirred for one hour and treated w th a mixture. of. 50.0 at lea,v 25.0.- of c n entrat hydro hlor c acid, and. 50.0 ml. of. water. The.- mixture. was. stirred dur ng the addition of the, ice. mixture. and was cooled by intermittently distilling, a portion ofjthe car bony. disulfide invaeuo. Ailter addition. of. all of. the: ice. mixture, the, carbon disu-lfide, remaining. was distilled in. mono and the. aqueous residue wa extracted, with 2 11.. of benzene. The. b.6117 zene. extract was dried oyer magnesium sulfate an evaporated. inrao o. o. a mall. volume. Se Qralv himes of. petroleum. other w re added. slow-- 3 to the concentrate whereupon.- a. y ll w o i-rstak line. pre pitate f d= enzooylzd keto la a ,3 5 -h ahi dr henzi dl ndole separated. he oreeipitate was filtered. Qfii. washed with: retroeum. other, and recrystallized. from. benzene-pe troleum ether mixture. After recrystallization from benzene-petroleum ether mixture, it melted at. about liidellflf 6;

Analysis Calculated for CisHisNGz: C; 77.96; H, 5.45;

.41 E undr 3,, 78i15.-;, 5- 1,; N 5d,:

Found: 0, 7597; H: 6.60; masts.

5 g. of 5-keto-1,2,2a,3,4,5-hexahydrobenz[cd]- indole were dissolved in 20 ml. of a mixture oi equal parts of ethanoland ethem and; dry hydrogen chloride was passed into the: solutibn until precipitation was complete: The precipitate 6 of 5-keto-1,2.2a,3,,5heXahydrobenz[ed]indole hydrochloride was filtered 011 and dried. It melted; with deexamplesition at; about: lea-201i. 61

Analysis;

Calculated; or CuI-IuNQHC i: C; 68011;. H

5.77- Eound; 3.63.2. H,,6..01

5' keto 1;,2,2,a, 3,4,5 hexahydrobenztcdlind'ole hydrobromide which was prepared in a manneranalogous to the preparation of the hydrochloride salt, melted with decomposition at about 212-215 e:

'- Analysis:

N=dcetyl i-lean-[Amiga-hexahydrobene- [Cdl'indole A solution of I. g. of 5.-keto I,2;2a,3,4,5i=hexa-- hydrobenzicd lindole inamixture of 12.5; ml. of

pyridine. and 12.5 ml. of; acetic. anhydride was. allowed to stand at room temperature for hour and was then warmed on a steam bath for about 15 minutes; The excess acetic: anhydrlde was decomposed: by the: addition of methanol, and the solution was evaporated to small volume in vacuo. The addition of a few milliliters. of water'- to the liquid residue caused the. precipita.-- tion of N-aeetyLEJi-ketoel,2,2a,3;4,5-hexahydroloenz['cd-lindole. The. precipitate was filtered off,

was washed successively with portions of dilute hydrochloric acid and Waller. and was recrystallized from ethanol. After recrystallization it melted at ab ut tilled-1118.5 0-- to stand atroom temperature for hourand was then heated on a steam bath for about 15 min utes. The excess: butyric anhydride was decomposed with methanol, and the solution was evaporated to small volume in vacuo. Upon addition of a few milliliters of water to the residue, N-loutyryl- 5-keto-1',2,2a;3,d,5 hexahyd robenz-Ecd] indole precipitated. The precipitate was filtered off; washed successively with dilute hydrochloric acid and water, recrystallized from ethanol, and dried-L After-recrystallization it melted at about r37-i5al3a-z5 Ca Analysis? Qaleulated iorCmItInNQz; 6", 74.04;; H, 7104;

153517 6; Round: 74.43:: H; 75:18:; N, 5H0

EXAMPLE 5 N-acetyl-5-keto-1,2,2a,3,4,5 hearahydrobenflcdl indole about 20 minutes on a steam bath. The excess of thionyl chloride was removed by evaporation in vacuo. The residue was dissolved in 50 ml. of dry nitrobenzene, and the nitrobenzene solution was added in a thin stream to a vigorously stirred suspension of g. of anhydrous aluminum chloride in 150 ml. of nitrobenzene, the reaction mixture being cooled externally to maintain the reaction temperature at about 10 to 20 C. The mixture was then stirred and heated at 50 C. for about 3 hours and allowed to stand at room temperature for a few hours. The reaction mixture was cooled to 20 C. and decomposed by the slow addition of a mixture of 100 g. of crushed ice, 100. ml. of concentrated hydrochloric acid, and 200 ml. of water. The lower nitrobenzene layer was separated and washed with three 150 ml. portions of 2N sodium hydroxide solution, and then with water. The washed nitrooenzene layer was separated and steam distilled to remove the nitrobenzene. The aqueous residue which contained a precipitate of N-acetyl B-keto-1,2,2a,3,4,5-hexahydrobenz [cdl indole was filtered, and the precipitate was washed with water and dried. The dry material melted at about 1745-1765 C.

EXAMPLE 6 Sodium p--(N-benzoyZ-1,2,2a,3,4,5 hexahydrobenzEcdlindoZyl) glycz'date 32.4 g. (0.83 gram atom) of potassium were dissolved in a mixture of 800 ml. of dry tertiary butanol and 700 ml. of dry benzene maintained under nitrogen. The solvents were removed in vacuo, and the potassium t.-butoxide was suspended in 1500 ml. of a mixture of equal volumes of dry benzene and dry toluene. The mixture was maintained under an atmosphere of nitrogen, and cooled in an ice bath, and to it were added 136 g. (0.49 mol) of N-benzoyl-5-keto-1,2,2a,3,4,5- hexahydrobenzicdlindole. To the mixture while being cooled in the ice bath 106 g. (0.85 mol) of ethyl chloroacetate were added dropwise with stirring over a period of 10 minutes. The cold solution was stirred for minutes, was warmed to room temperature and stirred for 15 minutes, and finally was heated and refluxed for 15 minutes. The mixture was cooled rapidly and treated with a few hundred grams of ice. The aqueous layer was separated, and the organic layer was washed successively with 1 l. of water, 1 l. of 1.5 N sulfuric acid, 1 1. of 0.7 N sulfuric acid, 1 l. of water and 1 l. of saturated sodium bicarbonate solution. The solution was dried over anhydrous magnesium sulfate, and the solvents were evaporated in vacuo. The syrupy glycidic ester remaining was dissolved in 1200 ml. or" absolute ethanol, and to the solution were added slowly with shaking ml. of 12.5 N sodium hydroxide solution. The mixture was allowed to stand for 20 minutes after which it was heated rapidly to HE- and held there for 5 minutes, and then cooled for about 1 hour. The sodium 18-5-(N-benzoyl-1,2,2a,3,4,5- hexahydrobenz[cdlindolyl) glycidate which sep- 8 arated was filtered ofi, washed with methanol and ether, and dried. The yield was 124 g., '71 percent of theory. The salt melted with decomposition at about 220-223" C. A sample prepared for analysis by recrystallization from a mixture of methanol and ether gave the following analysis:

Analysis:

Calculated for C2uH1eNO4Na: N, 3.92; Na, 6.44 Found: N, 3.85; Na, 6.65

EXAMPLE 7 Semicarbazone of N-benzoyl-5-formyZ-1,-2,2a,3-

tetrahydrobenz cd] indole 5 g. (0.014 mol) of sodium e-5-(N-benzoyl-1,2,- 2a,3,4,5-hexahydrobenz [cdlindolyD glycidate was mixed with ml. of dimethylformamide. To the mixture were added 4.5 g. (0.014 mol) of pyridine hydrobromide perbromide. The mixture was warmed to 60 and was then allowed to stand at room temperature for 3 hours. To it was added a previously prepared solution of 4.2 g. of semicarbazide hydrochloride and 3.6 g. (0.042 mol) of anhydrous sodium acetate in 35 ml. of dimethyl formamide, and the mixture was heated on a steam bath for 1 hour. The dimethylformamide was evaporated in vacuo, the dark syrupy residue was treated with water, and the amorphous product which separated was filtered, and washed well with water. The precipitate was dissolved in a minimum of hot glacial acetic acid, the solution was treated with decolorizing carbon, and diluted with two volumes of methanol. After chilling to about 5 C. for a few hours a crystalline precipitate of the semicarbazone of N-benzoyl-5- formyl-1,2,2a,3 tetrahydrobenzEcdlindole separated. The precipitate was filtered off and washed with small amounts of methanol and ether. The yield was 2.95 g., 61 percent of theory. It melted with decomposition at about 232-233 C.

Analysis:

Calculated for C20H18N402: C, 69.35; H, 5.24;

N, 16.18 Found: C, 69.15; H, 5.24; N, 16.20

The use of acetic acid as a solvent in the above reaction in place of dimethyl iormamide yields the same product in somewhat smaller yield.

EXAMPLE 8 Enol acetate 0 N-beneoyZ-5-formt/Z-1,2,2a,3,4,5 hexahydrobenelcdlindole 35.7 g. (0.1 mol) of sodium {3-5-(N-benzoyl- 1,2,2a,3,4,5-hexahydrobenz[cdlindolyl glycidate, were mixed with 15 g. of potassium acetate, 400 ml. of acetic anhydride, and 50 ml. of glacial acetic acid, and the mixture was refluxed for one hour. The solution was concentrated in vacuo to a syrup, traces of acetic anhydride were decomposed with a little methanol, and the solvent again removed in vacuo. The crystalline product consisting of the enol acetate of N-benzoyl-5- formyl-1,2,2a,3,4,5-hexahydrohenz[cdlindole was taken up in water containing a little methanol, filtered, dried and recrystallized from 200 ml. of a mixture of equal parts of benzene and petroleum ether. The yield was 15.5 g. It melted at about 158-162 C.

Analysis:

Calculated for C21H19NO3Z C, 75.65; H, 5.74;

N, 4.20 Found: C, 75.50; H, 5.77; N, 4.45

9 Semz'carbazone of N-benzoyl--formyl-1,2,2a,3-

tetrahydrobenzEcdlzndole 3.3 g. of the enol acetate were dissolved in ml. of glacial acetic acid, and 3.2g. of pyridine hydrobromide perbromide were added. The mixture was heated to 'C., cooled to 30, and mixed with 3.3 g. of semicarbazide hydrochloride and 3.0 g. of potassium acetate. The reaction mixture was shaken well, heated to treated with 5 ml. of water, and then kept at a temperature of C. for hour. The solvent was evaporated in vacuo, and water was added. The insoluble semicarbazone of N-benzoyl-5-iormyll,2,2a,3tetrahydrobenz[cdlindole was filtered ofi, washed with water, and recrystallized from a mixture of acetic acid and methanol. The yield was 1.0 g. The product melted with decomposition at about 233-234 C. The melting point showed no depression when mixed with sample of the semicarbazone prepared from the .lglycidic acid sodium-salt. 1

EXAMPLE 10 N-benzoyl-5-form'yl-1,2,2a,3-tetrahydrobenz- Ecdlindole 22.9 g. of the 'semi'carbazone of N-benzoyl-S- formyl-1,2,2a,3-tetrahydrobenz[cdlindole were mixed with 160 g. of redistilled pyruvic acid, 230 ml. of chloroform and 10 m1. of water. The solution was shaken until homogeneous and allowed to stand for 3 hours. It was diluted with 200ml. of chloroform and washed with three 300 ml. portions of water and with two 300 ml. portions of saturated sodium bicarbonate solution. The chloroform solution was dried over anhydrous magnesium sulfate, treated with decolorizing carbon, and concentrated to dryness in vacuo. The crystalline residue of N-benzoyl-5-formyl- 1,2,2a,3-tetrahydrobenz[cdlindole was digested with m1. of hot ethanol, cooled, filtered, and washed with methanol and ether. The yield was 16.1 g-., "85 percent of theory. It melted at about 171-174 C. After recrystallization of a sample from ethanol, it melted at'about 177-178 Analysis:

Calculated for CmHmNOz': C, 78.87; H, 5.23;

. N, 4.84 Found: C, 78.29; H, 5.73; N, 4.44 5-formyl-1,2,2aj3 tetrahydrobenzlcdlindole is obtained from the Nben'zoyl derivative-by refluxing a mixture of the latter compound and-com centrated hydrochloric acid until complete solution results. Evaporation of the solution to dryness yields a mixture of the hydrochloride acid addition salt of 5-iormyl-1,2,2a,3-tetrahydrobenz- 'lcdlindole and benzoic acid. The mixture is treated with ether to dissolve the benzoic acid and leave the salt as a residue.

Treatment of a solution of the salt in water with an equivalent of sodium bicarbonate yields the free 5-formyl-1,2,2a,3-tetrahydrobenz[cdlindole. Acid addition salts of the base are prepared by reacting the base with an equivalent of acid by any of the customary procedures.

N-acyl derivatives of 5-formyl-1,2,2a,3-tetrahydrobenz[cd]indole are prepared by reacting the indole compound with the acyl halide oranhydride, examples of which are butyric anhydride, toluic acid chloride, cyclopentyl carboxylic acid chloride, and the like. Alternatively, in place of the N-benzoyl derivative of 5-keto-1.2,2a,3,4,5- liexahydrobenzlicdlindole, other N-acyl coml9 pounds-aster example the propionyl caproyl, cyclohexanoyl etc. can be subjected to the rocedures of Examples -6 to 9 inclusive to produce an N-acyl-5-formyl-1,2,2a,3-tetrahydrobenz-[cdlindole.

1-1 a-MeiEflZ B-5-'(NfbitbQZ-I,2,22Z,3,3l,'5-7Litd hydrob'en'z [0d] iizdolyl) ylyezuemmze 6.7 g. of potassium were dissolved in 300 ml. of dry tertiary butyl alcohol, and the excess solvent was evaporatedinvacuo. The potassium tertiary butylate was dissolved in 300 m1. of dry benzene, and to the solution were added 27.7 g. of N-benzoyl' 5 -;k -eto l-,-2-,2a,-3,4,5 hexahydrobenzEcdlindole. The mixture was cooled in ice under nitrogen, and to it were added dropwise with stirring over aperiod of about 5 minutes 15.4 g. of a-chioropropionitrile. The cooled mixture was stirred for 30 minutes, was refluxed for one hour, and was cooled and diluted with ice water. The benzene layer which separated was recovered and washed sequentially with water, dilute hydrocholoric acid, water, and saturated sodium bicarbonate solution, and was dried over anhydrous magnesium sulfate. The benzene was distilled in vacuo, and the syrupy residue of a-methyl-fi-fi- (N benzoyl 1,2,2a,3,4,5 iiid'olyD 'gl-yciddnitrile crystallized rrom a mixture or hitr'om'ethane and methanol; crystalline product was filtered off, washed with inetha'iloland dfied. "The yield was 10.6 E, 32 percent br theory. It melted "at about 147-150 C. A sample recrystallized from methanol-nitromethane about IFS-158 C.

Analysis:

Calculated forC21H1aN2Oz: C, 76.34; H, 5.49; N, 8.48

Found: 0, 76. 19; 5163; N, 8.41

EXAMPLE 12 N-benaoyl-5-ace'tyi ii,2,2a,3-tetrahydrobenelcdlmdoie A solution of 65.3

mixture melted at g. of a-methyl-B-5-(N- glycidonitril'e in 750'1'1'11. of benzene and 7-50-1211. of absolute ether was cooled, and 210 g. of dry hydrogen chloride were passed into it with stirring and continued cooling. The solution was allowed to stand for 24 hours after which the solvents were removed completely in vacuo at 100 C., leaving a residue of N-benzoyl-5-acetyl- 5-ohloro-1,2,2a,3,4,5 he'XahydrobenzEcdlindoleoyanohydrin. 750 ml. of collidine were added to the crude cyanohydrin, and the solution was refluxed for houn The col-lid-ine was removed in vacuo and 700 ml. of chloroform were added to the residue. The solution was washed successively with 1 l. of water with two 1 1. portions of N"liydrochloric acid, with 1 l. of water and with a saturated sodium bicarbonate solution. The chloroform solution was dried over anhydrous magnesium sulfate, and the chloroform was evaporated in vacuo. The crystalline product consisting of N-benzoyl-5-aoetyl-l,2,2a,3-tetrahydrobenzEcdlindole was taken up in petroleum ether and filtered. The yield was 43.5 73 percent of theory. It melted at about 174-175" C. A sample melting at about HES-188 C. was obtained by recrystallizing the material from benzene.

Analysis:

Calculated for C20H17NO2: C, 79.18; H, 5.65;

N, 4.62 Found; C. 78.46; H. 5.35.; N, 1.9a

hexahydrobenz [cd] 11 From the N-benzoyl compound the non-benzoylated compound and its acid addition salts are prepared by the procedures set forth in Example 10.

Other -acyl-1,2,2a,3 tetrahydrobenzicdlindoles are obtained by employing an a-chloroalkyl cyanide other than oz-ChlOIOPI'OPlOIlltI'lIE as described in Example 11. Thus for example, butyronitrile, capronitrile and the like can be employed to provide B-acyl derivatives which contain a longer alkyl chain.

.As was the case with 5-formyl-1,2,2a,3-tetrahvdrobenzEcdJindole, other N-acyl derivatives can be employed instead of the N-benzoyl derivative, such being of the type described in connection with the 5-formyl compound in Example 10.

I claim:

1. A compound represented by the formula in which R represents a member of the group consisting of hydrogen, an acyl radical of a lower alkyl carboxylic acid and an acyl radical of a monocarbocyolic aromatic carboxylic acid, and R1 represents a member of the group consisting of hydrogen and a, lower alkyl radical.

2. A compound represented by the formula in which alk represents a lower alkyl group. 3. A compound represented by the formula (EH3 r o elk-PJ-N in which alk represents a. lower alkyl group.

4. A compound represented by the formula O GH3 N 5. A compound represented by the formula i alk- N in which all: represents a lower alkyl group.

6. A compound represented by the formula n l I CnHr-C- V 7. A compound represented by the formula OTHER REFERENCES Uhle, Jr. Am. Chem, Soc., vol. 71, pp. 761-766 (1949). 

1. A COMPOUND REPRESENTED BY THE FORMULA 